Inherited Prostate Cancer

Prostate cancer is the most common nondermatologic cancer in males in the United States.¹ Incidence and mortality rates vary significantly between countries. In the United States, the lifetime risk of developing prostate cancer is approximately 1 in 7, with an incidence similar to that of breast cancer. In 2015, it is estimated that prostate cancer will be diagnosed in 220,800 men and invasive breast cancer will be diagnosed in 231,840 women.¹ However, unlike breast cancer, men with prostate cancer are rarely tested for inherited risk.

Risk factors for prostate cancer include increasing age, African American race, and family history. Similar to most cancers, at least 10% of prostate cancers are associated with an inherited risk. Notably, it is believed that prostate cancer may have the highest heritability of any cancer, with 10% being a significant underestimate.^2,3 The first reports of an inherited component of prostate cancer appeared in the literature in the 1950s and 1960s.^2,4 Since then, many studies have demonstrated the existence of prostate cancer susceptibility genes. The first twin studies demonstrating heritability were reported in 1997, with Lichtenstein and colleagues reporting in 2000 that 42% of prostate cancer risk may be accounted for by heritable factors.⁵ A more recent twin study reported heritability as high as 58%.⁶

Although the heritability index for prostate cancer is high, the number of genes definitively linked to prostate cancer has been low, partly owing to its genetic heterogeneity. In the past 2 decades, numerous segregation and linkage analysis studies have been performed, and both autosomal dominant and recessive modes of transmission have been reported.⁷ However, traditional linkage analysis has not provided much insight into the genes involved in prostate cancer risk.⁸ Linkage analysis has many limitations in complex diseases like prostate cancer and, as a result, false positives and negatives occur. Therefore, many of the chromosomal regions reported to be candidates are not consistently demonstrated. Genome-wide association studies, which tend to identify genetic variants with a lower risk than variants uncovered by linkage studies, have identified more than 70 prostate cancer susceptibility loci. As expected, the majority are common in the general population and low penetrant. However, they may explain 30% of familial prostate cancer risk. It is believed these single-nucleotide polymorphisms (SNPs) are multiplicative. Therefore, although the odds ratios of individual SNPs may not be high enough to have predictive value, the combination of multiple SNPs might, with the men at greatest risk possibly having a 4.7-fold increased risk.⁹ Due to advances in technology, the challenges associated with screening for a large number of genes are being overcome; however, this does not necessarily mean testing is clinically useful.

Several syndromes and genes have repeatedly been shown to be associated with prostate cancer risk. These include hereditary breast and ovarian cancer syndrome (BRCA1/BRCA2), Lynch syndrome (MLH1, MSH2, MSH6, PMS2, EPCAM), HOXB13, NBN, and CHEK2. The genes conveying the greatest risk are BRCA2 and the HOXB13 G84E variant. Whereas BRCA2 mutations are associated with a 2- to 6-fold increased risk for prostate cancer, the association of prostate cancer with BRCA1 mutations is less defined. Additionally, individuals with BRCA mutations tend to have a more aggressive type of prostate cancer and be diagnosed at a younger age than those in the general population.¹⁰

One of the most recent prostate cancer risk findings is the G84E mutation in HOXB13. Men with this mutation have been shown to have a 33% to 60% risk of prostate cancer to age 80 years, compared with 12% in the general population.^11,12 To date, families with the G84E mutation have had men with early-onset prostate cancer or multiple cases of prostate cancer. Prostate cancer appears to be the main risk and the mutation does not appear to affect prognosis; however, data are still limited, as testing for the mutation is in its infancy.¹³ The mutation is found in approximately 5% of prostate cancer families, primarily in those of European descent.¹⁴

Similarly, men with Lynch syndrome have a 2- to 5-fold increased risk for prostate cancer,¹⁰ and there appear to be gene-specific risks, with MSH2 mutations conferring the highest risk. Similar to other tumors with mismatch repair deficiency, prostate cancer tumors associated with Lynch syndrome are more likely to have tumor-infiltrating lymphocytes.¹⁵ Studies are inconsistent regarding the age of onset and aggressiveness, but most show them to be similar to the general population. Finally, mutations in NBN, associated with the autosomal recessive condition Nijmegen breakage syndrome, and in CHEK2 have also been demonstrated to confer an approximately 3-fold increased risk for prostate cancer, although the literature is more limited.^16,17 Mutations in NBN may possibly result in a more aggressive phenotype.¹⁷

Although the clinical utility of prostate cancer risk testing is not clear, it is important to keep in mind that several of these syndromes are well-described and have medical interventions for other associated cancers. For example, Lynch syndrome is associated with an increased risk for multiple cancers, including colon cancer. In one study, more than 1 in 3 men with prostate cancer and Lynch syndrome presented with prostate cancer as their first or only cancer diagnosis.¹⁵ Thus, screening prostate cancer survivors for Lynch syndrome could help increase the identification of the syndrome and possibly prevent a new primary cancer as well as help identify at-risk family members.

Most prostate cancer in the United States is diagnosed via the use of prostate-specific antigen (PSA) screening. However, the results of 2 randomized studies suggested that data are insufficient to recommend the routine use of PSA screening in the general population. PSA screening is a controversial topic, with various opinions on who should undergo screening and at what age,^10,18 although it is unlikely that anyone would deny PSA screening to a man with a family history.² For those with a family history, genetic testing may help further provide risk stratification in targeted screening and prevention programs. Preliminary results from the IMPACT study have already demonstrated a positive correlation. This study found a positive predictive value in BRCA2 carriers that was double the positive predictive value in the general population for prostate biopsies.¹⁹ Thus, it is suggested that gene status should also be incorporated into screening algorithms. Additionally, carriers of BRCA with ovarian cancer have been found to benefit from poly (ADP-ribose) polymerase inhibitors. Their use is being evaluated in other cancers, such as prostate cancer, and appears to be promising.²⁰ Therefore, it is possible that genetic status might affect not only surveillance options but also treatment options for prostate cancer.

References

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